Valemetostat + Atezolizumab + Bevacizumab for Liver Cancer

Overseen By Pamela M Hardwick

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Alabama at Birmingham

Must not be taking: CYP3A inducers, P-gp inhibitors

Disqualifiers: Pregnancy, Cardiovascular disease, Autoimmune disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 42

45 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot use certain medications like moderate or strong CYP3A inducers, strong CYP3A and/or P-gp inhibitors, or chronic NSAIDs. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug combination Valemetostat + Atezolizumab + Bevacizumab for liver cancer?

The combination of atezolizumab and bevacizumab has been shown to improve overall survival and progression-free survival in patients with advanced liver cancer compared to the drug sorafenib, which was a standard treatment. This combination was approved by the FDA for liver cancer treatment, indicating its effectiveness. ^{1 2 3 4 5}

Is the combination of Valemetostat, Atezolizumab, and Bevacizumab safe for humans?

Atezolizumab and Bevacizumab have been used together safely in patients with liver cancer, but common side effects include high blood pressure, tiredness, and protein in the urine. Bleeding was more common in patients taking this combination compared to another treatment. There is no specific safety data available for Valemetostat in this combination. ^{1 3 6 7 8}

What makes the drug combination of Valemetostat, Atezolizumab, and Bevacizumab unique for liver cancer?

This drug combination is unique because it adds Valemetostat, a novel component, to the already established first-line treatment of Atezolizumab and Bevacizumab for advanced liver cancer, potentially offering a new approach to improve outcomes. ^{1 7 9 10 11}

What is the purpose of this trial?

This is a phase Ib/II, dose escalation and dose expansion study of valemetostat (DS-3201) with atezolizumab and bevacizumab in patients advanced Hepatocellular carcinoma (HCC) who did not receive prior systemic therapy for advanced HCC.

Research Team

Mehmet Akce, MD

Principal Investigator

University of Alabama at Birmingham

Eligibility Criteria

This trial is for adults with advanced Hepatocellular carcinoma (HCC) who haven't had systemic therapy for their condition. Details on specific inclusion and exclusion criteria are not provided, but typically participants need to meet certain health standards.

Inclusion Criteria

I have at least one cancer spot that hasn't been treated yet.

My liver is functioning well despite my illness.

My liver cancer is at an advanced stage where direct treatments won't work.

Exclusion Criteria

Pregnant persons, nursing persons, or persons of childbearing potential unwilling to employ adequate contraception

I had a treatment focused on my liver less than 28 days ago.

Subjects with psychological, social, familial, or geographical factors or substance abuse that would prevent regular follow-up

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b Treatment

Participants receive valemetostat (DS-3201) orally daily, plus atezolizumab 1200 mg IV and bevacizumab 15 mg/kg IV on day 1 of each 21-day cycle. A 3+3 dose escalation design is used to define the MTD or RP2D.

Up to 36 months

Every 21 days (in-person)

Phase II Treatment

Participants receive valemetostat (DS-3201) orally daily at MTD/RP2D, plus atezolizumab 1200 mg IV and bevacizumab 15 mg/kg IV on day 1 of each 21-day cycle.

Up to 36 months

Every 21 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 48 months

Treatment Details

Interventions

• Atezolizumab
• Bevacizumab
• Valemetostat Tosylate (DS-3201b)

Trial Overview The study tests valemetostat combined with atezolizumab and bevacizumab in treating liver cancer. It's a two-part trial: first, finding the right dose of valemetostat (dose escalation), then seeing how well it works at that dose (dose expansion).

Participant Groups

Group I: Phase II: Valemetostat + Atezolizumab 1200 mg + Bevacizumab 15 mg/kg Experimental Treatment 3 Interventions

During Phase II, study participants will receive valemetostat (DS-3201) orally daily at MTD/RP2D, plus atezolizumab 1200 mg intravenously (IV) on day 1, and bevacizumab 15 mg/kg IV on day 1 of each cycle.

Group II: Phase 1b: Valemetostat + Atezolizumab 1200 mg + Bevacizumab 15 mg/kg Experimental Treatment 3 Interventions

In Phase 1b patients will receive valemetostat (DS-3201) orally daily at their assigned dose level, plus atezolizumab 1200 mg intravenously (IV) on day 1, and bevacizumab 15 mg/kg IV on day 1 of each cycle. During Phase 1b, a 3+3 dose escalation design will be utilized to define the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) with starting dose of valemetostat 150mg by mouth daily.

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Findings from Research

Atezolizumab in combination with bevacizumab has been approved by the FDA for treating unresectable hepatocellular carcinoma (HCC), showing improved overall survival (OS) and progression-free survival (PFS) compared to sorafenib, with a hazard ratio of 0.58 for OS.

The combination therapy resulted in a median PFS of 6.8 months versus 4.3 months for sorafenib, although it was associated with a higher incidence of hemorrhage (25% vs. 17%), highlighting the need for careful monitoring of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Atezolizumab Plus Bevacizumab for the Treatment of Patients with Advanced Unresectable or Metastatic Hepatocellular Carcinoma. Casak, SJ., Donoghue, M., Fashoyin-Aje, L., et al.[2022]

The combination of atezolizumab and bevacizumab has been shown to significantly increase overall survival in patients with advanced hepatocellular carcinoma (HCC) compared to sorafenib.

The FDA's approval of this combination therapy marks a significant advancement in the treatment of HCC, potentially changing how the disease is managed across all stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus Bevacizumab: A Novel Breakthrough in Hepatocellular Carcinoma. Castet, F., Willoughby, CE., Haber, PK., et al.[2022]

In a study of 194 Chinese patients with unresectable hepatocellular carcinoma, the combination of atezolizumab and bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) compared to sorafenib, with a hazard ratio for OS of 0.44 and for PFS of 0.60.

While the combination treatment showed promising efficacy, it also resulted in a higher incidence of grade 3-4 adverse events (59.1%) compared to sorafenib (46.6%), with hypertension being the most common severe side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus Bevacizumab versus Sorafenib in the Chinese Subpopulation with Unresectable Hepatocellular Carcinoma: Phase 3 Randomized, Open-Label IMbrave150 Study. Qin, S., Ren, Z., Feng, YH., et al.[2022]

Atezolizumab combined with bevacizumab demonstrated good efficacy in treating advanced hepatocellular carcinoma (HCC), with a pooled overall response rate of 26% and a median overall survival of 14.7 months based on a review of 23 studies involving 3168 patients.

The treatment was well-tolerated, with 83% of patients experiencing any grade adverse events, and 30% experiencing grade 3 or higher adverse events, indicating that while side effects are common, the combination therapy remains a viable first-line option for advanced HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab treatment for advanced hepatocellular carcinoma in the real world: a single-arm meta-analysis. Gao, X., Zhao, R., Ma, H., et al.[2023]

Atezolizumab plus bevacizumab significantly improves progression-free survival (PFS) compared to lenvatinib in patients with unresectable hepatocellular carcinoma (uHCC), based on a meta-analysis of 8 studies involving 3690 patients.

Patients receiving atezolizumab plus bevacizumab experience fewer severe adverse events (grade 3/4) compared to those treated with lenvatinib, indicating a better safety profile, although lenvatinib may be more effective for overall survival in non-viral patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a systematic review and meta-analysis. Liu, J., Yang, L., Wei, S., et al.[2023]

In a multicenter study of 121 patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Ate/Bev), the objective response rate was 24% and the disease control rate was 76%, demonstrating real-world efficacy similar to phase III trial results.

The most common severe side effect was an increase in aspartate aminotransferase levels (10.7%), and factors like elevated baseline neutrophil-to-lymphocyte ratio were linked to poorer progression-free and overall survival, indicating the need for careful monitoring in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab in Korean patients with advanced hepatocellular carcinoma. Cheon, J., Yoo, C., Hong, JY., et al.[2022]

In a study of 191 patients with unresectable hepatocellular carcinoma (HCC), the combination therapy of atezolizumab and bevacizumab showed similar overall survival and progression-free survival rates in older patients (≥65 years) compared to younger patients (<65 years), indicating its efficacy across age groups.

The safety profile of the combination therapy was comparable between older and younger patients, with similar rates of treatment-related adverse events, including severe adverse events, suggesting that older patients can tolerate this treatment as well as younger patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma. Vithayathil, M., D'Alessio, A., Fulgenzi, CAM., et al.[2023]

In a study of 286 patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab, treatment-related hypertension was linked to better progression-free survival, with a median of 12.6 months compared to 6.5 months for those without hypertension.

Conversely, treatment-related fatigue was associated with shorter overall survival, indicating that while hypertension may signal a positive response to treatment, fatigue could indicate poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events as potential predictive factors of therapeutic activity in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab. Tada, T., Kumada, T., Hiraoka, A., et al.[2023]

In a study of 766 patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab, those who met the IMbrave150 trial inclusion criteria had significantly longer overall survival (16.3 months) compared to those who did not (14.3 months).

Among patients who did not meet the IMbrave150 criteria, those with a better liver function (ALBI grade 1) experienced a notable survival benefit, with a median overall survival of 16.7 months compared to 5.9 months for those with ALBI grade 2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Data for Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma: How Does Adherence to the IMbrave150 Trial Inclusion Criteria Impact Prognosis? Rimini, M., Persano, M., Tada, T., et al.[2023]

In a study of 41 patients with advanced hepatocellular carcinoma who failed first-line treatment with atezolizumab and bevacizumab, the median post-first-line survival was 5.9 months, significantly influenced by liver function status after treatment failure.

Patients with better liver function (Child-Pugh A) had a median survival of 9.6 months compared to only 3.8 months for those with Child-Pugh B and 1.2 months for Child-Pugh C, highlighting the importance of liver reserve and the benefit of receiving second-line therapy, which improved survival to a median of 8.0 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognosis and treatment pattern of advanced hepatocellular carcinoma after failure of first-line atezolizumab and bevacizumab treatment. Chen, CT., Feng, YH., Yen, CJ., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Atezolizumab Plus Bevacizumab for the Treatment of Patients with Advanced Unresectable or Metastatic Hepatocellular Carcinoma. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Atezolizumab plus Bevacizumab: A Novel Breakthrough in Hepatocellular Carcinoma. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Atezolizumab plus Bevacizumab versus Sorafenib in the Chinese Subpopulation with Unresectable Hepatocellular Carcinoma: Phase 3 Randomized, Open-Label IMbrave150 Study. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab treatment for advanced hepatocellular carcinoma in the real world: a single-arm meta-analysis. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a systematic review and meta-analysis. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab in Korean patients with advanced hepatocellular carcinoma. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Adverse events as potential predictive factors of therapeutic activity in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Predictive biomarkers of survival in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab treatment. [2023]

10. France pubmed.ncbi.nlm.nih.gov

Real-World Data for Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma: How Does Adherence to the IMbrave150 Trial Inclusion Criteria Impact Prognosis? [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Prognosis and treatment pattern of advanced hepatocellular carcinoma after failure of first-line atezolizumab and bevacizumab treatment. [2022]